Deserpidinol and salts thereof



nnsnnrmrnor. AND SALTS THEREOF Harold Balding MacPhillamy, Madison, N.J., assignor to Ciba Pharmaceutical Products, Inc., Summit, N. J., acorporation of New Jersey No Drawing. Application January 13, 1955,Serial No. 481,720

5 Claims. (Cl. 260-486) This invention relates to a new carbinol, namedhereinafter deserpidinol; its salts, and the processes for thepreparation thereof. I have found that deserpidinol can be obtained bysubjecting organic sulfonic acid esters of alcohol esters of deserpidicacid to certain reducing agents described below. Deserpidic acid has theformula Des wherein Des represents the divalent organic radical of theempirical formula CH24ON2 bound to the hydroxyl and carboxyl group indcserpidic acid which contains a basic tertiary nitrogen atom.

The esters of deserpidic acid used as starting materials may be obtainedaccording to copending application Serial No. 471,519, filed November26, 1954, of Paul R. Ulshafer by degradation of the alkaloiddeserpidiue, described in copending application Serial No. 468,161,filed November 10, 1954, now abandoned of Paul R. Ulshafer, todeserpidic acid, esterification of the carboxyl group and subsequentlyconversion of the hydroxyl group into a hydroxyl group esterified withan organic sulfonic acid.

According to my investigations deserpidinol has the formula OHzOH Deswherein Des has the aforesaid meaning. It has valuable properties; itcan be used, for example, as active ingredient in sunburn compositionson account of its absorption of U. V.-light of the wave length rangecritical for the development of sunburn. Furthermore, it is a valuableintermediate for the preparation of compounds having related structure,which can be used in a wide field of applications, for example inmedicine. According to my investigations deserpidinol can be converted,for example, into rauwolscinyl alcohol [Chatterjee and Pakrashi, Scienceand Culture (India), 19, 109 (1953)] by treatment with ether-splittinghydrolyzing agents, for example hydrobromic or hydriodic acid.

The process of the invention comprises treating organic sulfonic acidesters of alcohol esters of deserpidic acid with reducing agents capableof simultaneously replacing the esterified hydroxyl group by a hydrogenatom and reducing the esterified carboxyl group to the hydroxy methylgroup so as to form deserpidinol. As a reducing agent there isespecially useful hydrogen in statu nascendi. Preferably the reaction iscarried out with lithium aluminum hydride in an appropriate solvent,such as tetrahydrofurane or ether. As starting materials, there areadvantageously used aryl sulfonic acid esters of alkyl deserpidates,such as O-p-toluene sulfonyl methyl deserpidate.

Depending on the working conditions employed, the new compound isobtained as the free base or in the form of its salts. From the salts,the free base may be States Patent and one-half hours at liberated byconventional methods. The base can be converted into its acid additionsalts, by reaction with acids, for example hydrohalic acids, sulfuricacid, nitric acid, phosphoric acid, alkane sulfonic acids, alkylsulfuric acids, hydroxyethane sulfuric acid, acetic acid, oxalic acid,citric acid, tartaric acid and the like.

The new compound can be made up into sun screen compositions accordingto the customary methods employed in making such preparations.Preferably it may be incorporated into a hydrophilic ointment whichcontains for example, glycols such as propylene glycol, higher aliphaticalcohols such as stearyl alcohol, white petrolatum, distilled water andthe like.

The following example will serve to illustrate the invention, therelationship of parts by weight to parts by volume being the same as thegram to the milliliter and the temperatures given in degrees centigrade.

Example 2 parts by weight of p-toluene sulfonyl methyl deserpidate in 25parts by volume of dry, freshly distilled tetrahydrofurane are addeddropwise to a stirred slurry of 1.5 parts by weight of lithium aluminumhydride in 60 parts by volume of dry tetrahydrofurane. The mixture isthen refluxed for five hours, after which 50 parts by volume of waterare added cautiously with cooling. The tetrahydrofurane is distilled oftand the aqueous suspension filtered. The residue is washed with waterand then extracted five times with hot acetone. The combined acetoneextracts are heated to boiling, filtered through a filter cell andevaporated to dryness. The oily residue is taken up in chloroform,washed twice with water, and the chloroform extract evaporated todryness. Trituration with methanol yields colorless crystals. The thusobtained deserpidinol can be recrystallized from methanol and melts at232236 with decomposition; its optical rotation is [u] =2i2(chloroform). The empirical formula of deserpidinol is C21HzsG2N2. ItsU. V.-spectrum shows a maximum at )\=282 (6:7670) (in chloroform).

Deserpidinol can be converted into rauwolscinyl alcohol as follows:

A suspension of 0.5 part by weight of deserpidinol in 5 parts by weightof freshly distilled hydrobromic acid is heated while introducing astream of nitrogen for one The material is dissolved during thereaction. The reaction mixture is poured into water and theprecipitation filtered. The precipitation is dissolved in methanol,aqueous ammonia is added and the mixture added to the filtrate which hasalso been made basic. The thus obtained solution is extracted withchloroform and the chloroform extract evaporated to dryness. It isdissolved in a small volume of acetone and kept in a refrigeratorovernight. The thus obtained rosettes of rauwolscinyl alcohols aresolvated and melt with loss of solvent and decomposition unsharplybeneath After sublimation rauwolscinyl alcohol melts at 229-231".

The p-toluene sulfonyl methyl deserpidate used as starting material maybe obtained as follows:

To 0.5 part by weight of desperidine is added a solution of 0.65 part byweight of sodium in 25 parts by volume of methanol. The mixture isrefluxed under nitrogen for one hour during which the desperidine alldissolves. After cooling, the solution is concentrated in vacuo to avolume of about 10 parts by volume. 30 parts by volume of water areadded and then concentrated hydrochloric acid in a dropwise manner untilthe solution is strongly acidic. It is then extracted with 15 parts byvolume of ether and re-extracted with 3 portions each of 10 parts byvolume of ether. The aqueous phase is then made basic with concentratedaqueous ammonia and extracted with 15 parts by volume of methylenechloride and re-extracted with 3 portions each of 10 parts by volume ofmethylene chloride. The combined methylene chloride extracts are driedover anhydrous potassium carbonate and concentrated in vacuo to givemethyl deserpidate as a pale, yellow solid froth which analyzes for theempirical formula C22H2804N2. In the same manner, by employing dryethanol or butanol instead of methanol, the corresponding alkyldesperidates are obtained.

To a solution of 0.46 part by weight of methyl deserpidate (dried bydistilling toluene from it twice) in parts by volume of freshlydistilled pyridine is added dropwise and with cooling 0.46 part byweight of p-toluenesulfonyl chloride in 1 part by volume of dry benzene.1 part by volume of pyridine is used to rinse the reagent into thereaction flask which is securely stoppered and allowed to stand at 5 for5 days. The reddish solution is poured into approximately 50 parts byvolume of ice and water. 12 parts by volume of 5 percent aqueous ammoniaare added and the semi-solid precipitate is triturated for about 5minutes. The mixture is then extracted with three portions of methylenechloride of 50 parts by volume, 15 parts by volume and parts by volume.The combined methylene chloride extracts are washed three times withsmall portions of a cold sodium chloride solution, dried over anhydrouspotassium carbonate and evaporated in vacuo to a semi-crystallineresidue. 0.63 part by weight of this is dissolved in methylene chloride,filtered through approximately 0.02 part by weight of activated charcoalon a diatomaceous earth filter cell, evaporated and crystallized from 4parts by volume of benzene. Additional material is obtained from thebenzene mother liquors. Recrystallization from methanol givesO-(p-toluenesulfonyl)-methyl deserpidate, melting at 226-228".

Deserpidine may be obtained as follows:

500 parts by weight of dried, finely ground roots of Rauwolfia canescensare extracted batch-wise with methanol at its boiling point, using thefollowing volumes and times, and filtering each extract while hot: 2,000parts by volume, 1 hour; 1,000 parts by volume, 45 minutes; 1,000 partsby volume, 30 minutes; 1,000 parts by volume, 30 minutes. The extractsare combined and evaporated in vacuo to 75 parts by volume of thicksyrupy solution. After the addition of 75 parts by volume of methanoland 150 parts by volume of acetic acid of per cent strength withadequate mixing, the solution is extracted with 2 portions each of 100parts by volume of hexane. The combined hexane extracts are extractedwith 15 parts by volume of acetic acid of 15 percent strength. Thelatter extract is added to the above acetic acid phase which is thenextracted with 3 portions each of 75 parts by volume and 1 portion of 50parts by vol ume of ethylene chloride. The first 3 extracts are combinedand washed with parts by volume of 2 N sodium carbonate solution andthen with 60 parts by volume of distilled water. These washing solutionsare saved and used for the washing of the 4th and final ethylenechloride extract. The combined ethylene chloride extracts are dried oversodium sulfate, filtered and evaporated in vacuo to a constant weight ofa tan, frothy solid. I part by weight of this residue is dissolved in1.5 parts by volume of warm methanol and the solution cooled to 5 C. for18 hours, whereby crystallization of reserpine sets in. After filteringfrom the crystallized reserpine and washing with cool methanol, thefiltrate is freed of so1- vent in vacuo. 2 parts by weight of theresulting redbrown solid froth are triturated with 2 portions each of 25parts by volume of benzene and filtered each timc. The benzene insolublematerial is saved for further treatment. The benzene soluble fraction ispoured onto a column of 40 parts by weight of activated alumina (Woelm,Activity Grade I), which is then eluted first with 3 portions each of 50parts by volume of benzene and then with 6 portions each of 50 parts byvolume of benzene-acetone (9:1), the first of which benzene-acetoneportions had been used for extraction of the above mentioned benzeneinsoluble material. The second of the 6 benzene-acetone elutionfractions on removal of the solvents gives a light tan solid froth whichon crystallization from methanol gives colorless prismatic needles ofslightly impure deserpidine. Rechromatographing of 1 part by weight ofthis substance on 20 parts by Weight of activated alumina (Woelm,Activity Grade I) using benzene and benzene containing 0.1 percentmethanol as eluting agents followed by crystallization from methanolgives colorless prismatic needles of pure deserpidine, melting at228-232 C.

What is claimed is: I

1. A member of the group consisting of deserpidinol and acid additionsalts thereof.

2. Deserpidinol.

3. Salts of the compound claimed in claim 1.

4. Process for the preparation of a new carbinol comprising reducingO-p-toluene sulfonyl methyl deserpidate with lithium aluminum hydride soas to produce deserpidinol.

5. Process for the preparation of a new carbinol com prising reducing anO-aryl-sulfonyl alkyl deserpidatc with lithium aluminum hydride to formdeserpidinol.

References Cited in the file of this patent Beilstein, Org. Chem, vol.XXIII (2nd Supp. 1954) pp. 409-10.

Schlitter et al.: Experientia, vol. XI, No. 2, Feb. 15, 1955, pp. 6465.

Cerletti et al.: Experientia, vol. XI, No. 3, Mar. 15, 1955, pp. 98-99.

1. A MEMBER OF THE GROUP CONSISTING OF DESERPIDINOL AND ACID ADDITIONSALTS THEREOF.